No abstract

These results reveal for the first time that resistin is a highly attractive therapeutic target in ameliorating elevated serum low-density lipoprotein and, thereby, atherosclerotic cardiovascular diseases in obese humans.

Rationale:Obese individuals are at high risk for developing atherosclerosis primarily attributable to elevated plasma concentrations of apolipoprotein (apo)B-containing particles, including very-low-density lipoprotein (VLDL). Plasma levels of the adipose tissue adipokine resistin are increased in human obesity, and resistin expression is positively correlated with coronary atherosclerosis and VLDL levels.Objective: We sought to determine for the first time whether resistin directly stimulates human hepatocyte production of apoB-containing particles and to elucidate the mechanisms responsible. Methods and Results:Treatment of human hepatocytes with resistin at levels observed in human obesity stimulated apoB secretion up to 10-fold, because of increased microsomal triglyceride transfer protein (MTP) activity and decreased expression/phosphorylation of proteins in the insulin signaling pathways (insulin receptor substrate-2, Akt, and extracellular signal-regulated kinase). Resistin also increased hepatocyte lipid content by stimulating de novo lipogenesis via the SREBP1 and SREBP2 pathways. Furthermore, obese serum with elevated resistin levels induced greater hepatocyte stimulation of apoB secretion than lean human serum, an effect that was ameliorated by antibody immunoprecipitation removal of serum resistin. Key Words: obesity Ⅲ dyslipidemia Ⅲ apolipoprotein B Ⅲ hepatic T he worldwide prevalence of obesity has reached epidemic proportions, with more than 1 billion individuals worldwide characterized as being obese. 1 In North America alone, 1 in 3 adults is obese. 2 This is a problem because obese individuals are at greatly elevated risk for developing atherosclerotic cardiovascular disease (ASCVD), the leading cause of death in North America. 3 Fundamental to the accelerated rate of ASCVD development in obese individuals is the presence of dyslipidemia. Despite numerous advances in the treatment of dyslipidemia, up to 60% of abdominally obese individuals have metabolic dyslipidemia: an elevation in plasma levels of triglycerides, a reduction in plasma high-density lipoprotein (HDL) cholesterol, and an increase in plasma numbers of low-densitylipoprotein (LDL) particles, which are small and dense. 4,5 The primary lipoprotein abnormality that drives the development of metabolic dyslipidemia in obesity is an elevation in plasma levels of very-low-density-lipoprotein (VLDL), which precedes and is metabolically linked to each component of metabolic dyslipidemia. 6,7 Elevated VLDL in obesity is primarily attributable to increased hepatic secretion of VLDL triglycerides and apolipoprotein (apo)B. 6,7 Although several mechanisms have been proposed, including whole-body and hepatic insulin resisOriginal received December 9, 2010; revision received January 20, 2011; accepted January 24, 2011. In December 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days. tance and increased free fatty acid (FFA) flux to the liver, these factor...